DNA topoisomerases are enzymes involved in the modification of the DNA-supercoiling during replication or transcription. These enzymes bind to single-stranded or double-stranded DNA and they cut the phosphate backbone of the DNA such that the DNA strand is untangled or unwound. At the end of the replication or transcription processes, the enzymes themselves reseal the DNA backbone.
DNA topoisomerases are classified as type I when they cut a single strand of a DNA double helix and as type II when they cut both strands of a DNA double helix.
Bacterial type II topoisomerases comprise DNA gyrase and topoisomerase IV (TopoIV), which are heterotetrameric enzymes concurrently present in almost all the prokaryotic cells. Both the enzymes are necessary for DNA replication and, hence, for bacterial cell growth and division.
Bacterial type II topoisomerases are proven antibacterial targets, in particular of compounds belonging to fluoroquinolone class.
Fluoroquinolones are broad-spectrum antibacterial drugs that play an important role in treatment of bacterial infections, especially hospital-acquired infections and infections in which resistance to other classes of antibacterial drugs is suspected. Fluoroquinolones act by inhibiting the DNA gyrase in Gram negative bacteria and the topoisomerase IV in Gram positive bacteria.
However, resistance to fluoroquinolones emerged in recent years due to mutations that altered either the active site of the drug targets DNA gyrase and topoisomerase IV or the drug accumulation. In addition, resistance to quinolones can be mediated by plasmids that produce the Qnr protein, which protects the quinolone targets from inhibition (G. A. Jacoby, CID, 2005:41, Suppl. 2, SD120-S126).
According to the World Health Organization, the antimicrobial resistance (AMR) is the resistance of a microorganism to an antimicrobial drug to which it was originally sensitive. Resistant bacteria are able to withstand attack by antibiotics and antibacterial drugs, so that standard treatments become ineffective and infections persist increasing risk of spread to others.
Mitton-Fry M. J. et al. (Bioorg. Med. Chem. Lett., 23, 2010, 2955-2961) developed novel quinolone derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV. Given the importance of stepwise target mutations in the clinical history of fluoroquinolones resistance, the authors felt strongly that providing inhibition of TopoIV alongside DNA gyrase was critically important. According to the authors, such dual-targeting activity should slow the rate of resistance emergence in the clinic, since organism which mutate DNA gyrase to avoid inhibition would still be susceptible to killing via TopoIV inhibition.
Surivet J. P. et al. (J. Med. Chem. 2013, 56, 7396-7415) reported the design of novel bacterial dual DNA gyrase and TopoIV inhibitors comprising a tetrahydropyran core and demonstrated that dual inhibition of DNA gyrase and TopoIV is required to minimize the rate of resistance development.
Zayane Marwa et al. (Journal of Enzyme Inhibition and Medicinal Chemistry 2016, 31(6):1566-1575) reported the design and synthesis of 4-methylumbelliferone derivatives with antimicrobial, anticoagulant, and anticholinesterase activity.
WO 2006/105289 relates to heterocyclic compounds, more particularly pyrazole compounds, which were tested for inhibition of both DNA gyrase and topoisomerase IV.
WO 02/072572, WO 2006/021448, WO 2008/139288, WO 2009/141398, WO 2010/081874, WO 2010/084152, WO 2013/068948, WO 2013/080156, WO 2016/027249, WO 2016/096631 and WO 2016/096686 disclose heterocyclic compounds endowed with antimicrobial activity.
WO 96/10568 and WO 2012/003418 disclose heterocyclic compounds endowed with other therapeutic activity.